Synthesis of a tridentate ligand for use in TiIV-catalyzed acetate aldol addition reactions

Article abstract of DOI:10.1002/hlca.200390092

A facile, practical synthesis and resolution of (±) -2′-amino-[1,1′-binaphthalen]-2-ol (1) is described, as well as the preparation of the tridentate Schiff base ligand 2 derived from condensation of 1 with 3-bromo-5-(tert-butyl)salicylaldehyde, which has been used in catalytic enantioselective acetate aldol addition reactions.

Full text of DOI:10.1002/hlca.200390092

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Helvetica Chimica Acta ± Vol. 86 (2003)
IV
Synthesis of a Tridentate Ligand for Use in Ti -Catalyzed Acetate Aldol
Addition Reactions
by Robert A. Singer, Jane R. Brock, and Erick M. Carreira*
Laboratorium f¸r Organische Chemie, ETH-Z¸rich, CH-8093 Z¸rich
Dedicated to Professor Jack D. Dunitz on the occasion of his 80th birthday
A facile, practical synthesis and resolution of (Æ)-2'-amino-[1,1'-binaphthalen]-2-ol (1) is described, as well
as the preparation of the tridentate Schiff base ligand 2 derived from condensation of 1 with 3-bromo-5-(tert-
butyl)salicylaldehyde, which has been used in catalytic enantioselective acetate aldol addition reactions.
Introduction. ± The identification and development of novel ligands and ligand
scaffolds have, in part, fueled advances in catalytic asymmetric synthesis. Indeed, an
important outcome of the vast number of studies in this field has been the realization
that the reactivity of transition-metal complexes can be substantially and dramatically
altered on the basis of the associated ligands [1]. These effects are most notably
manifested in the kinetic profile of a reaction, including reaction rate, catalyst loading,
and turnover frequency, as well as in various aspects of selectivity (enantio-, diastereo-,
and chemoselectivity). Advances in the design and synthesis of chiral catalysts for
enantioselective-reaction methodology are dependent on the availability of inexpen-
sive, optically active starting materials. Many of these are prepared from naturally
occurring diols, amino acids, amino alcohols, and carbohydrates [2].
Chiral metal complexes derived from C -symmetric substituted 1,1'-binaphthalenes
2
have proven to be remarkably effective as catalysts for asymmetric synthesis. The most
widely used substituted binaphthalenes include [1,1'-binaphthalene]-2,2'-diol (BI-
NOL), 2,2'-bis(diphenylphosphinyl)-1,1'-binaphthalene (BINAP), and [1,1'-binaph-
thalene]-2,2'-diamine [3]. For each of these, both enantiomers are readily available or
readily prepared. However, derivatives of unsymmetrical, substituted 1,1'-binaphtha-
lenes such as (‡)-(R)-2'-amino-[1,1'-binaphthalene]-2-ol (1) have only recently been
examined for the preparation of chiral metal complexes [4 ± 7]. We have documented
the use of (‡)-(R)-1 in the preparation of a tridentate ligand 2, whose derived titanium
complex 3 is effective in catalytic enantioselective aldol addition reactions [5]. The
unsymmetrical 1,1'-binaphthalene possesses several salient features as a precursor to
chiral ligands: 1) availability of both enantiomers; 2) ease of derivatization; 3)
amenability to incremental variations in the overall electronics and sterics of the metal-
ligand complex.
We have described a tridentate Schiff-base ligand prepared from (‡)-(R)-2'-amino-
[
1,1'-binaphthalen]-2-ol ((‡)-(R)-1) and 3-bromo-5-(tert-butyl)salicylaldehyde (ˆ 3-
IV
bromo-5-(tert-butyl)-2-hydroxybenzenecarbaldehyde). The orange Ti complex 3
derived from 2, (i-PrO) Ti, and 3,5-di-(tert-butyl)salicylic acid catalyzes (2 mol-%) the
4

Helvetica Chimica Acta ± Vol. 86 (2003)
1041
acetate aldol addition of O-trimethylsilyl O-methyl ketene acetal and aldehydes in
IV
good yields and high levels of asymmetric induction (Scheme). The Ti complex in this
IV
catalytic process displays some unique features relative to other Ti complexes that
have been reported to date pertaining to its wide substrate scope [8]. Indeed, the
catalytic process has found numerous applications, including our own synthesis of
macrolactin A [9]. Synthesis of the active complex required a practical preparation of
optically active, pure 2'-amino-[1,1'-binaphthalen]-2-ol (1); however, unlike BINOL
and [1,1'-binaphthalene]-2,2'-diamine, the resolution of (Æ)-2'-amino-[1,1'-binaphtha-
lene]-2-ol has received less attention [6][7]. The utility of this ligand in aldol-addition
reactions along with potential other applications that may be identified in the future
compel us to document herein the preparation of the tridentate ligand 2 [10].
Scheme 1
Results and Discussion. ± The coupling of naphthalen-2-amine and naphthalen-2-ol
can be carried out on a large scale to give racemic 2'-amino-[1,1'-binaphthalen]-2-ol.
We have found that slight modifications of the procedure reported by Ko cœ ovsk y¬ and co-
workers reproducibly afford 1 [6]. Thus, stirring a solution of naphthalen-2-amine,
naphthalen-2-ol, PhCH NH , and CuCl ¥ 2 H O in deoxygenated MeOH over 48 h
2
2
2
2

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Helvetica Chimica Acta ± Vol. 86 (2003)
afforded 2'-amino-[1,1'-binaphthalen]-2-ol in 65% yield. In the subsequent experiments
involving the resolution of 2'-amino-[1,1'-binaphthalen]-2-ol with camphorsulfonic
acid, we observed batch-dependent results. We speculated that this was a function of
trace amounts of residual Cu salts, as judged by slight coloration of the product. This
problem was addressed by noting that a second washing of the isolated product with
acid (HCl) and base (NH OH) assures removal of Cu salts from the product, as judged
4
by coloration of the aqueous layers, and, thus, facilitates the subsequent enantiomeric
resolution. The resolution is carried out by treating a rapidly stirred solution of (Æ)-2'-
amino-[1,1'-binaphthalen]-2-ol in PhCl/abs. EtOH 5 :1 at 658 with (R)-camphor-10-
1
sulfonic acid ). After initial formation of a precipitate, the well-stirred solution was
allowed to slowly cool to room temperature over 1 h and allowed to stand for an
additional hour. The isolated filtrate was washed three times with PhCl to afford the
camphorsulfonate salt. After the filter cake was suspended in a mixture of CH Cl and
2
2
5
% aqueous NaHCO solution, the mixture was stirred rapidly for 10 min, over which
3
time the organic phase became homogeneous. From the organic phase was isolated (‡)-
(
R)-2'-amino-[1,1'-binaphthalen]-2-ol in 97% ee. This was conveniently assayed by
1
conversion to the corresponding Mosher derivative and analysis of the H-NMR
spectrum (CDCl ) and integration of MeO peaks (major d 2.95, minor 2.81 ppm). A
3
subsequent recrystallization of the product (97% ee) from benzene afforded (‡)-(R)-1
(
(
73%) with an optical purity of 99% ee as a crystalline solid. Since both (À)-(R)- and
‡)-(S)-camphorsulfonic acids are inexpensive and readily available, either (‡)-(R)-
or (À)-(S)-2'-amino-[1,1'-binaphthalene]-2-ol (1) can be accessed by the resolution
described.
The synthesis of the Schiff-base ligand 2 illustrates the ease with which 1 can be
derivatized. The conversion of optically pure 1 to the tridentate ligand was readily
effected upon condensing with the substituted salicylaldehyde. Thus, treatment of 1
with 3-bromo-5-(tert-butyl)salicylaldehyde in absolute EtOH at reflux for 24 h afforded
a bright orange crystalline solid, 2, in 83% yield. This material, in combination with di-
IV
(
tert-butyl)salicylic acid, is suitable for use as a ligand with Ti to furnish a complex that
may be used as a catalyst for enantioselective addition reactions of aldehydes and silyl
ketene acetals.
We have described a facile preparation of the tridentate ligand 2 for use in
enantioselective acetate aldol addition reactions. Given the ease with which we have
demonstrated access to multi-gram quantities of 2 by the procedure we have described,
this should facilitate its use not only as reported but also possibly in further
applications.
Experimental Part
(
Æ)-2-Amino-1,1'-binaphthalen]-2-ol ((Æ)-1). MeOH (1.4 l) is deoxygenated in a 2-l flask by bubbling N
through for 1 h. In a separate 1-l flask are placed naphthalen-2-ol (5.00 g, 34.7 mmol) and naphthalen-2-amine
Caution, handle with care; 5.00 g, 34.7 mmol) in 400 ml of the deoxygenated MeOH. PhCH NH (37.2 g,
47 mmol) is placed in a 500-ml flask and dissolved in 200 ml of deoxygenated MeOH. To the remaining
deoxygenated methanol is added CuCl ¥ 2H O (14.8 g, 86.7 mmol). Once all the CuCl is dissolved by stirring,
the soln. of PhCH NH is added via cannula. After stirring the Cu and PhCH NH soln. for 10 min at r.t., the
2
(
3
2
2
2
2
2
2
2
2
2
1)
We have observed that a 3:1 toluene/i-PrOH mixture may be used as an alternative to PhCl/EtOH.

Helvetica Chimica Acta ± Vol. 86 (2003)
1043
soln. of naphthalen-2-ol and naphthalen-2-amine is added via cannula. The soln. is stirred at 238 for 48 h. The
precipitate formed is collected with a fritted funnel and washed twice with 50 ml of MeOH. The filter cake is
stirred with 100 ml of 37% aq. HCl and 100 ml of H
added slowly followed by 500 ml of H O. The precipitate is isolated by filtration and washed twice with 50 ml of
O. The solid is stirred again with 50 ml of 37% aq. HCl and 100 ml of H O for 10 min. A 30% aq. soln. of
NH OH (70 ml) is slowly added to the soln. and is then diluted with 300 ml of H O. The precipitate is collected
by filtration and washed twice with 50 ml of water. The powder obtained is dried in vacuo to give 6.44 g (65%) of
2 4
O for 30 min. Then 150 ml of a 30% aq. NH OH soln. is
2
H
2
2
4
2
(
Æ)-1.
(
‡)-(R)-2-Amino-[1,1'-binaphthalen]-2-ol ((‡)-1). In an 100-ml flask is placed (Æ)-1 (5.00 g, 17.5 mmol) in
5
5.5 ml of PhCl and 11.1 ml of abs. EtOH. The soln. is heated to 658 with rapid stirring and (R)-camphor-10-
sulfonic acid (4.24 g, 18.3 mmol, recrystallized from AcOEt prior to use) is added. The dark-colored mixture
became homogeneous immediately after addition of the (R)-camphor-10-sulfonic acid. Stirring is continued,
and heating is maintained at 658 for 30 min, during which time a precipitate began to form. The well-stirred soln.
is then allowed to gradually cool to r.t. over 1 h and allowed to stand for an additional hour. The precipitate
formed is isolated by filtration and washed three times with 4 ml of PhCl. The filter cake is suspended in a
mixture of 50 ml of CH
which time the org. phase became homogeneous. The mixture is transferred to a separatory funnel, and the org.
layer is separated. The aq. layer is extracted with another 15 ml of CH Cl . The combined org. layers are dried
Na SO
2 2 3
Cl and 25 ml of a 5% aq. NaHCO soln. The mixture is stirred rapidly for 10 min, over
2
2
(
2
4
) and concentrated in vacuo to give 2.20 g (88%) of (‡)-1 in 97% ee. A small sample of the unpurified
solid was converted to the corresponding (S)-MTPA ester (4-(dimethylamino)pyridine, (R)-MTPACl, CH
Analysis by H-NMR spectroscopy revealed that it had been formed in 97% ee (ratio of diastereoisomers
determined from integration of MeO peaks in H-NMR (300 MHz, CDCl
2
Cl
2
).
1
1
3
): major d 2.95, minor 2.81 ppm).
Recrystallization of the product (97% ee) from 20 ml of benzene affords 1.83 g (73%) of (‡)-1 with an
1
9
19
D
optical purity of 99% ee. M.p. 1698. [a]
D
ˆ ‡122 (c ˆ 1.04, THF) ([5]: m.p. 171-38; [a]
ˆ ‡116, for 97% ee).
3
-Bromo-5-(tert-butyl)salicylaldehyde (ˆ 3-Bromo-5-(tert-butyl)-2-hydroxybenzenecarbaldehyde Mg
(
3.60 g, 150 mmol) and Mg(OMe) methoxide (682 mg, 0.750 mmol) are placed in a 500-ml flask in 71 ml of
2
anh. MeO and 30 ml of toluene to be heated to reflux for 1.5 h. To the white, cloudy soln. is added 4-(tert-
butyl)phenol (37.0 g, 250 mmol), and heating is continued for another h. An additional 100 ml of toluene is
added, and the MeOH/toluene azeotrope is then removed by distillation (b.p. 638) from the clear, yellow soln.
Once the distillation temp. rises above 1008, heating is temporarily stopped for addition of another 50 ml of
toluene to the white suspension. Paraformaldehyde (23.0 g, 750 mmol) is then added in 3 ± 5 g batches over 1 h
with resumed heating. The thick, yellow soln. is stirred at 1108, and the low-boiling materials are removed by
distillation throughout the addition of the paraformaldehyde. After all the paraformaldehyde is added, heating
is continued for another 2 h. The soln. is then cooled to r.t., and diluted with 50 ml of toluene and 250 ml of a
1
0% aq. H
extracted with another 50 ml of toluene. The combined org. layers are washed with 150 ml of a 10% aq. soln. of
SO and 100 ml of a sat. aq. NaCl soln. After drying (Na SO ), the org. extracts are concentrated. The residue
is a yellow oil (31.4 g), which consists of 80% 5-(tert-butyl)salicylaldehyde and 20% 4-(tert-butyl)phenol. To a
50-ml flask containing a soln. of the crude 5-(tert-butyl)salicylaldehyde (31.4 g, 176 mmol) in 90 ml of glacial
AcOH is added Br (11.4 ml, 220 mmol) dropwise. The orange soln. is allowed to stir for 24 h at 238. The soln. is
then diluted with 100 ml of H O to precipitate the product. The crystals are collected by suction filtration and
washed with H
2 4
SO soln. The mixture is stirred for 1.5 h at 608. The org. layer is separated, and the aq. layer is
H
2
4
2
4
2
2
2
2
O (3 Â 50 ml). The yellow solid is recrystallized from hexane/AcOEt 10 :1 to give 27.1 g (42%
overall) of yellow crystals. M.p. 818.
Schiff Base (‡)-2. In a 25-ml flask, a soln. of (‡)-1 (1.00 g, 3.50 mmol) and 3-bromo-5-(tert-
butyl)salicylaldehyde (1.08 g, 4.21 mmol) in 10 ml of abs. EtOH is heated at reflux for 24 h. After removal of
the volatiles in vacuo, the product is isolated by flash chromatography on 100 ml of silica gel (4-cm diameter
column) with hexane/AcOEt 4 :1. The resulting orange powder is dried under vacuum (1 mm Hg) for 12 h to
1
9
give 1.53 g (83%) of (‡)-2. M.p. 1648. [a]
D
ˆ ‡22.8 (c ˆ 1.00, CHCl
3
).
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1
Received February 6, 2002